Systemic lupus erythematosus (SLE) is characterized by a loss of immunologic tolerance to a multitude of self-antigens that results in systemic organ inflammation. Despite decades of research, the underlying genetic basis of lupus is clearly complex and remains poorly understood. Unbiased screens of the human genome using genome-wide association (GWAS) approaches have successfully identified over 30 genomic regions in SLE case-control groups primarily of European ancestry. Despite this surge of new genes associated with SLE, the GWAS approach has been unable to identify the precise causal variants that underlie the statistical associations, thus hampering functional translation of this information into improvements in the diagnosis and management of patients with SLE. Our laboratory has acquired the resources and experience necessary to move beyond GWAS to causal variant discovery and characterization. As a measure of our success we have identified functional variants responsible for association with SLE in the region of TNFAIP3 and BLK. The primary objective of this project is to define the functional mechanisms of causal variants and haplotypes in three SLE risk genes, TNIP1, UBE2L3 and IRF5. The work proposed herein will expand the number of SLE risk genes for which functional causal variants are known and understood. A mechanistic understanding of causal variants and the haplotypes that carry them is critically needed to formulate a cogent view of the SLE genetic landscape and to catalyze progress in the diagnosis and treatment of SLE. For this proposal, we have assembled a team of skilled investigators that span a variety of scientific and clinical disciplines including rheumatology, endocrinology, nephrology, genetics, molecular biology, proteomics, biostatistics and bioinformatics. Key resources available to this project that are unique to OMRF and developed by our group over the previous five years include: 1) high density SNP datasets in over 8,300 SLE cases and 7,400 controls across 4 major racial populations, 2) a targeted resequencing database of over 700 subjects of European and African ancestry, 3) an assembled database of over 1000 locally available research subjects broadly consented for participation in genetic studies and completely genotyped for all known SLE risk genes, 4) new state-of-the-art clinical facilities for patient characterization and sample procurement, and 5) access to cutting edge molecular and genomic technologies. We are confident that these rich datasets and our cumulative experience uniquely position our group to lead the effort in causal variant discovery in SLE. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus is a debilitating autoimmune disease that has failed to keep pace with the development of new therapies. While the environmental triggers of SLE remain enigmatic, we have witnessed an explosion in new genetic data. The next major challenge for SLE genetics will be to translate these genetic discoveries into biologic mechanisms that simulate the development of new diagnostics and therapeutics in the clinical care of patients with SLE, and this project is dedicated to that objective.